Prototype anticancer drugs show concerning side effects in animals
Some small molecule inhibitors are not suitable as cancer treatments, but will be important probes for further research.
Healthy cells in the human body can become cancerous if they gain genetic mutations that allow them to rapidly grow and divide. Some types of cancer respond better to drug treatments than others and tumours often develop resistance to a particular drug treatment after a while. Because of this, researchers are always searching for new molecules to develop into anticancer drugs.
Recently, a team of researchers identified some small molecules that could inactivate two closely related proteins called CDK8 and CDK19. CDK8 is essential for the WNT signalling pathway — which enables cells to communicate with one another — and has been extensively studied in various cancers. Previous studies indicate that this protein can either promote or inhibit the growth of tumours, depending on the type and stage of the cancer. Furthermore, CDK8 regulates a type of molecular switch called a “super-enhancer”, which controls the activity of many genes. In contrast, the role of CDK19 in cells was not as well understood.
Paul Clarke, Maria-Jesus Ortiz-Ruiz and colleagues investigated whether two different classes of small molecules that target CDK8 and CDK19 (referred to as “prototype CDK8/19 drugs”) could inhibit the growth of cancers, and whether they have any harmful side effects on healthy cells.
For the experiments, human cancer cells were implanted into mice. Treating these mice with prototype CDK8/19 drugs inhibited the activity of CDK8 and CDK19 in the cancer cells and slowed the growth of colorectal tumours. A type of blood cancer called acute myeloid leukaemia was particularly sensitive to the drugs. However, Clarke, Ortiz-Ruiz and colleagues also observed that the prototype drugs altered the activity of many genes with roles in healthy tissues such as immune, bone and stem cells. Further experiments in mice and cells grown in the laboratory confirmed that these prototype drugs have adverse effects on healthy intestinal and bone marrow stem cells and trigger changes to immune cells. These concerning side effects were also evident when the prototype drugs were tested in rats and dogs. Furthermore, the experiments indicate that there is not a suitable range of doses of these drugs in which the therapeutic benefits outweigh the toxic side effects.
Clarke, Ortiz-Ruiz and colleagues conclude that the clinical development of CDK8/19 drugs will be extremely challenging and that their prototype drugs would not currently be suitable for use as cancer treatments. However, the small molecules they describe will be important probes in research to study exactly how CDK8/19 regulate gene activity in both healthy cells and cancers.
To find out more
Read the eLife research paper on which this eLife digest is based: “Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases” (December 9, 2016).
